Criteria Specification (CSpec) Registry is intended to provide access to the Criteria Specifications used and applied by ClinGen Variant Curation Expert Panels and biocurators in the classification of variants.
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| Criteria & Strength Specifications
|
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|---|---|---|---|---|
| PVS1 | ||||
|
Original ACMG Summary
Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.
Caveats: • Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7). • Use caution interpreting LOF variants at the extreme 3’ end of a gene. • Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact. • Use caution in the presence of multiple transcripts.
VCEP Specifications:
PVS1_RNA See attached PVS1 decision tree, adapted from Walker, et. al. 2023 [PMID:37352859] for observed RNA splicing defects from functional splicing assays (minigene assay, RNA Sequencing, transcriptome analysis, etc) [PMID: 39418753]
Stand Alone
Very Strong
See “OTC VCEP PVS1 Decision tree” file
Default Point Value:
8
Modification Type:
Gene-specific
Strong
Default Point Value:
4
Modification Type:
Gene-specific
Moderate
See “OTC VCEP PVS1 Decision tree” file
Default Point Value:
2
Modification Type:
Gene-specific
Supporting
Default Point Value:
1
Not Applicable
|
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| PS1 | ||||
|
Original ACMG Summary
Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.
Example: Val->Leu caused by either G>C or G>T in the same codon. Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.
VCEP Specifications:
To avoid applying evidence for variants that potentially impact splicing, SpliceAI score must be checked for both the reported variant and the variant under review. PS1 at any strength is only applicable if spliceAI for both variants is ≤0.2 Stand Alone
Very Strong
Strong
Applicable when the previously reported variant is classified as Pathogenic using these OTC specifications.
Default Point Value:
4
Modification Type:
No change
Moderate
Applicable when the previously reported variant is classified as Likely Pathogenic using these OTC specifications.
Default Point Value:
2
Modification Type:
Gene-specific,Strength
Supporting
Default Point Value:
1
Not Applicable
|
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| PS2 | ||||
|
Original ACMG Summary
De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.
Note: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.
VCEP Specifications:
Stand Alone
Very Strong
Use ClinGen Sequence Variant Interpretation (SVI) Review Committee recommended scoring system, attached “PS2.PM6_Scoring”.
Default Point Value:
8
Modification Type:
Disease-specific,Gene-specific
Strong
Use SVI recommended scoring system, attached “PS2.PM6_Scoring”.
Default Point Value:
4
Modification Type:
Disease-specific,Gene-specific
Moderate
Use SVI recommended scoring system, attached “PS2.PM6_Scoring”.
Default Point Value:
2
Modification Type:
Disease-specific,Gene-specific
Supporting
Use SVI recommended scoring system, attached “PS2.PM6_Scoring”.
Default Point Value:
1
Modification Type:
Disease-specific,Gene-specific
Not Applicable
|
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| PS3 | ||||
|
Original ACMG Summary
Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.
Note: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established.
VCEP Specifications:
Stand Alone
Very Strong
Default Point Value:
8
Strong
PS3 at a strong level is not applicable for OTC enzyme activity assays. Please see PS3_Moderate and PS3_supporting below.
Default Point Value:
4
Modification Type:
Gene-specific,None,Strength
Moderate
Yeast growth assays -- applicable when growth of the ARG3 variant strain is ≤50% when compared to wildtype strains
Default Point Value:
2
Modification Type:
Gene-specific,Strength
Supporting
Yeast growth assays -- applicable when growth of the ARG3 variant strain is >50 and ≤65% when compared to wildtype strains Enzyme activity in non-patient derived cell lines -- applicable if enzyme activity of the variant under review is <20% compared to wildtype.
Default Point Value:
1
Modification Type:
Gene-specific,Strength
Not Applicable
|
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| PS4 | ||||
|
Original ACMG Summary
The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.
Note 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance. Note 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence.
VCEP Specifications:
Stand Alone
Very Strong
8 additional male or female probands observed - must meet PP4 criteria and/or have documented hyperammonemia or metabolic decompensation under physiological stress to be counted
Default Point Value:
8
Modification Type:
Gene-specific,Strength
Strong
4 additional male or female probands observed - must meet PP4 criteria and/or have documented hyperammonemia or metabolic decompensation under physiological stress to be counted
Default Point Value:
4
Modification Type:
Gene-specific,Strength
Moderate
2 additional male or female probands observed - must meet PP4 criteria and/or have documented hyperammonemia or metabolic decompensation under physiological stress to be counted
Default Point Value:
2
Modification Type:
Gene-specific,Strength
Supporting
One additional male or female proband observed - must meet PP4 criteria and/or have documented hyperammonemia or metabolic decompensation under physiological stress to be counted
Default Point Value:
1
Modification Type:
Gene-specific,Strength
Not Applicable
|
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| PM1 | ||||
|
Original ACMG Summary
Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.
VCEP Specifications:
Stand Alone
Very Strong
Strong
Default Point Value:
4
Moderate
The following residues are considered critical within OTC: Carbamoylphosphate binding site – amino acids: Ser-90, Thr-91, Arg-92, Thr-93, His-117, Arg-141, His-168, Gln-171, Leu-304, and Arg-330 Ornithine binding site – amino acids: Leu-163, Asn-198, Asn-199, Asp-263, Ser-267, Met 268 Catalytic site – amino acids: His-302, Cys-303, Leu-304 Conserved amino acids important for OTC structure and function: Arg-277 - Affect Km for ornithine [PMID: 9175746, 9065786] Pro-305 - cis-proline that stabilizes the HCLP motif [PMID: 9852088] Gly-269 - part of the mobile SMG loop [PMID: 8544185]
Default Point Value:
2
Modification Type:
Gene-specific
Supporting
Default Point Value:
1
Not Applicable
|
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| PM2 | ||||
|
Original ACMG Summary
Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.
Caveat: Population data for indels may be poorly called by next generation sequencing.
VCEP Specifications:
PM2 will be used at a supporting level of evidence per SVI guidance (https://www.clinicalgenome.org/site/assets/files/5182/pm2_-_svi_recommendation_-_approved_sept2020.pdf) Stand Alone
Very Strong
Strong
Moderate
Default Point Value:
2
Supporting
Applicable for variants in OTC with Grpmax Filtering Allele Frequency <0.000015 (0.0015%) AND ≤1 homo- or hemizygote in the most current version of gnomAD available at the time of curation. Rationale: The most common pathogenic variant in population databases is p.Arg40Cys, which is associated with late onset OTC Deficiency (PMID: 23209112, 7860066, 11260212, others) and present in 17 heterozygotes and 6 hemizygotes in gnomAD(v4.0.0) (Mino Allele frequency=0.001586% in European populations). Other commonly reported pathogenic variants (p.Arg277Trp, p.Arg141Gln, p.Arg141Ter) are rare or absent in population databases, therefore a threshold of 0.0015% is set for PM2_Supporting.
Default Point Value:
1
Modification Type:
Gene-specific
Not Applicable
|
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| PM3 | ||||
|
Original ACMG Summary
For recessive disorders, detected in trans with a pathogenic variant
Note: This requires testing of parents (or offspring) to determine phase. Stand Alone
Very Strong
Default Point Value:
8
Strong
Default Point Value:
4
Moderate
Default Point Value:
2
Supporting
Default Point Value:
1
Not Applicable
Comments:
Not applicable, as OTC is an X-linked gene and biallelic females are sufficiently rare
|
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| PM4 | ||||
|
Original ACMG Summary
Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.
Stand Alone
Very Strong
Strong
Default Point Value:
4
Moderate
PM4 is applicable as described for in-frame loss or gain of ≥1 amino acid but less than an entire exon. For in-frame deletions or insertions ≥1 exon, defer to PVS1 flowchart.
Default Point Value:
2
Modification Type:
No change
Supporting
Default Point Value:
1
Not Applicable
|
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| PM5 | ||||
|
Original ACMG Summary
Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.
Example: Arg156His is pathogenic; now you observe Arg156Cys. Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.
VCEP Specifications:
Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.
Stand Alone
Very Strong
Strong
Default Point Value:
4
Moderate
PM5 is applicable as described if the variant under review occurs at the same amino acid as a variant classified Pathogenic using these OTC specifications.
Default Point Value:
2
Modification Type:
No change
Supporting
PM5 is applicable as described if the variant under review occurs at the same amino acid as a variant classified Likely Pathogenic using these OTC specifications.
Default Point Value:
1
Modification Type:
No change
Not Applicable
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| PM6 | ||||
|
Original ACMG Summary
Assumed de novo, but without confirmation of paternity and maternity.
Stand Alone
Very Strong
Default Point Value:
8
Strong
Use PS2/PM6 criteria described under PS2. Occurrences of de novo and presumed de novo are summed for a final PS2/PM6 evidence strength.
Default Point Value:
4
Modification Type:
No change
Moderate
Use PS2/PM6 criteria described under PS2. Occurrences of de novo and presumed de novo are summed for a final PS2/PM6 evidence strength.
Default Point Value:
2
Modification Type:
No change
Supporting
Use PS2/PM6 criteria described under PS2. Occurrences of de novo and presumed de novo are summed for a final PS2/PM6 evidence strength.
Default Point Value:
1
Modification Type:
No change
Not Applicable
|
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| PP1 | ||||
|
Original ACMG Summary
Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.
Note: May be used as stronger evidence with increasing segregation data.
VCEP Specifications:
Stand Alone
Very Strong
Strong
≥5 informative segregations
Default Point Value:
4
Modification Type:
Gene-specific,Strength
Moderate
3-4 informative segregations
Default Point Value:
2
Modification Type:
Gene-specific,Strength
Supporting
2 informative segregations
Default Point Value:
1
Modification Type:
Gene-specific,Strength
Not Applicable
|
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| PP2 | ||||
|
Original ACMG Summary
Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.
Stand Alone
Very Strong
Strong
Moderate
Supporting
Default Point Value:
1
Not Applicable
Comments:
Not applicable, gnomAD (05/2021) expected missense 131.9, observed missense 89, for Z=1.33 (o/e =0.67).
|
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| PP3 | ||||
|
Original ACMG Summary
Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).
Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.
VCEP Specifications:
Stand Alone
Very Strong
Strong
Missense variants - REVEL score ≥0.932
Default Point Value:
4
Modification Type:
None
Moderate
Missense variants - REVEL score ≥0.773 and <0.932
Default Point Value:
2
Modification Type:
None
Supporting
Missense variants - REVEL score ≥0.644 and <0.773 Splice region and intronic variants - spliceAI delta score ≥0.20
Default Point Value:
1
Modification Type:
None
Not Applicable
|
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| PP4 | ||||
|
Original ACMG Summary
Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.
VCEP Specifications:
Stand Alone
Very Strong
Strong
Default Point Value:
4
Moderate
Proband phenotype points total ≥1.5 points
Default Point Value:
2
Modification Type:
Gene-specific,Strength
Supporting
Proband phenotype points total >0.5 to <1.5 points
Default Point Value:
1
Modification Type:
Strength
Not Applicable
|
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| PP5 | ||||
|
Original ACMG Summary
Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.
Not Applicable
This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.
PubMed : 29543229
|
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| BA1 | ||||
|
Original ACMG Summary
Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.
VCEP Specifications:
BA1 exception list for OTC:
Stand Alone
Allele frequency above 0.010000 (1.0%), Grpmax Filtering Allele Frequency OR ≥10 (female) homozygotes or (male) hemizygotes in the most current version of gnomAD available at the time of curation.
Default Point Value:
Not Applicable
Modification Type:
Gene-specific
Very Strong
Strong
Moderate
Supporting
Not Applicable
|
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| BS1 | ||||
|
Original ACMG Summary
Allele frequency is greater than expected for disorder.
VCEP Specifications:
BS1 exception list for OTC:
Stand Alone
Very Strong
Strong
An allele frequency >0.002000 (0.2%), Grpmax Filtering Allele Frequency in the most current version of gnomAD available at the time of curation. Note: Both BS1 and BS2 cannot be applied if the same dataset is used to assess population data
Default Point Value:
-4
Modification Type:
Gene-specific
Moderate
Default Point Value:
-2
Supporting
Default Point Value:
-1
Not Applicable
|
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| BS2 | ||||
|
Original ACMG Summary
Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.
VCEP Specifications:
BS2 exception list for OTC:
Stand Alone
Very Strong
Strong
The variant is observed in >5 (female) homozygotes or 5 (male) hemizygotes in the most current version of gnomAD available at the time of curation.
Default Point Value:
-4
Modification Type:
Gene-specific
Moderate
Default Point Value:
-2
Supporting
Default Point Value:
-1
Not Applicable
|
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| BS3 | ||||
|
Original ACMG Summary
Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.
VCEP Specifications:
Yeast growth assays in which the ARG3 open reading frame of a yeast strain is replaced with the OTC coding sequence, and site directed mutagenesis utilized to introduce variant of interest [PMID: 37146589] can be used at BS3_Moderate or BS3_Supporting based on the % of growth compared to strains containing wildtype ARG3 (see attached Functional Assay spreadsheet). Stand Alone
Very Strong
Strong
Default Point Value:
-4
Moderate
BS3_Moderate is applicable when growth of the variant strain is ≥80% when compared to strains containing the wildtype OTC gene.
Default Point Value:
-2
Modification Type:
Gene-specific,Strength
Supporting
Yeast growth assays in which the ARG3 open reading frame of a yeast strain is replaced with human OTC coding sequence, and site directed mutagenesis utilized to introduce variant of interest (PMID: 37146589) BS3_Supporting is applicable when growth of the variant strain is >65% and <80% growth when compared to strains containing the wildtype OTC gene.
Default Point Value:
-1
Modification Type:
Gene-specific,Strength
Not Applicable
|
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| BS4 | ||||
|
Original ACMG Summary
Lack of segregation in affected members of a family.
Caveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation.
VCEP Specifications:
Stand Alone
Very Strong
Strong
Default Point Value:
-4
Moderate
Default Point Value:
-2
Supporting
Presence of the variant under review in an unaffected male of a family if the age of the unaffected male is at or above the age of onset for other affected males in the family.
Default Point Value:
-1
Modification Type:
Gene-specific
Not Applicable
|
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| BP1 | ||||
|
Original ACMG Summary
Missense variant in a gene for which primarily truncating variants are known to cause disease.
Stand Alone
Very Strong
Strong
Default Point Value:
-4
Moderate
Default Point Value:
-2
Supporting
Default Point Value:
-1
Not Applicable
Comments:
Not applicable. Pathogenic missense variants have been documented for OTC deficiency.
|
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| BP2 | ||||
|
Original ACMG Summary
Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.
Stand Alone
Very Strong
Strong
Default Point Value:
-4
Moderate
Default Point Value:
-2
Supporting
Applicable in females for which OTC deficiency is diagnosed and the variant under review is identified in trans or in cis with a known pathogenic variant, or if the variant under review is identified in cis in a male with OTC deficiency.
Default Point Value:
-1
Modification Type:
None
Not Applicable
|
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| BP3 | ||||
|
Original ACMG Summary
In frame-deletions/insertions in a repetitive region without a known function.
Stand Alone
Very Strong
Strong
Default Point Value:
-4
Moderate
Default Point Value:
-2
Supporting
Default Point Value:
-1
Not Applicable
Comments:
Not applicable. OTC does not contain repetitive regions without known function.
|
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| BP4 | ||||
|
Original ACMG Summary
Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)
Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant.
VCEP Specifications:
Stand Alone
Very Strong
Strong
Missense variants - REVEL score ≤0.016
Default Point Value:
-4
Modification Type:
Gene-specific
Moderate
Missense variants - REVEL score >0.016 and ≤0.183
Default Point Value:
-2
Modification Type:
Gene-specific
Supporting
Missense variants - REVEL score >0.183 and ≤0.290 Synonymous variants – spliceAI delta score <0.1 if variant is not within the first or last three nucleotides of an exon.
Default Point Value:
-1
Modification Type:
Gene-specific,Strength
Not Applicable
|
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| BP5 | ||||
|
Original ACMG Summary
Variant found in a case with an alternate molecular basis for disease.
Stand Alone
Very Strong
Strong
Default Point Value:
-4
Moderate
Default Point Value:
-2
Supporting
Applicable when the variant of interest is identified in a male with an alternative molecular etiology of elevated hyperammonemia including biallelic pathogenic/likely pathogenic variants in autosomal recessive disease or a pathogenic/likely pathogenic variant for autosomal dominant or X-linked disease.
Default Point Value:
-1
Modification Type:
No change
Not Applicable
|
||||
| BP6 | ||||
|
Original ACMG Summary
Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.
Not Applicable
This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.
PubMed : 29543229
|
||||
| BP7 | ||||
|
Original ACMG Summary
A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.
VCEP Specifications:
Stand Alone
Very Strong
Strong
Applicable for potential splicing or intronic variants with experimental evidence demonstrating no splicing effect of the variant under review (BP7_strong (RNA).
Default Point Value:
-4
Modification Type:
No change
Moderate
Default Point Value:
-2
Supporting
Splicing / intronic variant -- applicable for intronic variants with spliceAI <0.10 if the variant under review is outside splice region +7/-21 nucleotides. Synonymous variants -- applicable when BP4_Supporting is met and only if the synonymous variant is outside the first base of an exon and last 3 bases of an exon.
Default Point Value:
-1
Modification Type:
No change
Not Applicable
|
||||
| Category | Point Ranges |
|---|---|
| Pathogenic | 10 |
| Likely Pathogenic | 6 - 9 |
| Uncertain Significance | 0 - 5 |
| Likely Benign | -6 - -1 |
| Benign | -7 |
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Questions or comments?
